When an animal switches between behavioral states, such as from quiet sleep to active (REM) sleep, and from active sleep to wakefulness, there are profound changes in almost all physiological systems. These changes occur rapidly, with an observable time base of seconds, although the responsible mechanisms are likely operating in the range of milliseconds. It is the purpose of this grant application to explore the processes that allow the animal to switch from one behavioral state to another. As the basis for exploring these processes, the PI is proposing to investigate the fashion in which non-NMDA-mediated EPSPs occur spontaneously in motoneurons during wakefulness and glycinergically-mediated IPSPs occur exclusively during active sleep. These patterns of motor excitation during wakefulness, and motor inhibition during active sleep, also arise in "response" to exogenous stimulation (i.e., activation of the sciatic nerve or the presentation of auditory stimuli) and to endogenous stimulation (i.e., by PGO waves) (see C. Progress Report/Preliminary Studies). How can these patterns of motor response-reversal take place with the only variable being the change of state of the animal? The PI's hypothesis is that at the moment of active sleep and for the duration of the state, a switching mechanism (or neuronal gate) is activated in the nucleus pontis oralis so that input to this region, that normally triggers motor excitation, now results in motor inhibition. The proposed neuronal gating mechanism that operates during active sleep is based upon the cholinergic activation of cells in the nucleus pontis oralis, the cholinergic inhibition of other cells in the nucleus pontis oralis and the disfacilitation of GABAergic interneurons. The PI further suggests that within the nucleus pontis oralis, and at each of the key relays along the active sleep-dependent motor inhibition system (i.e., the nucleus pontis oralis, the medullary motor inhibitory area and trigeminal motor nucleus), activity is enhanced by the action of neuromodulators. The final result is the excitation of glycinergic terminals that promote the postsynaptic inhibition of motoneurons exclusively during active sleep. The successful conclusion of the proposed studies will be the clarification of the manner in which neurotransmitters and neuromodulatory systems interact in an integrated fashion to change spontaneous and induced motor responses from excitation during wakefulness to inhibition during active sleep. Based upon these data, future studies will be designed to determine the extent to which neuromodulated neuronal gates (or switching mechanisms) participate in other state-dependent patterns of activity as well as in those processes that are responsible for switching between the behavioral states of sleep and wakefulness.